Biochemical neuroplasticity in the cerebellum after physical exercise: Systematic review and meta-analysis

Abstract

Background

Neuroplasticity is the central nervous system’s (CNS) capacity to adapt to injuries or environmental changes. Biochemical neuroplasticity is one such adaptation that may occur in response to physical exercise (PE). This systematic review and meta-analysis aimed to evaluate the effects of PE on cerebellar biochemical neuroplasticity.

Methods

Following the PICO strategy, this review included in vivo studies with small rodents (Population) subjected to well-defined PE protocols (Intervention) and compared to non-exercised controls (Comparator) to assess cerebellar biochemical alterations (Outcome). Studies published between January 1976 and July 2024 without language restrictions were searched in PubMed, Scopus, Web of Science, and Cochrane Central databases. Data were synthesized through meta-analyses and methodological quality was assessed by the SYRCLE risk of bias tool.

Results

Out of 3,107 records screened, six studies met the inclusion criteria for qualitative and quantitative analyses. All studies had a low or unclear risk of bias. Markers of biochemical neuroplasticity assessed included superoxide dismutase (SOD), catalase (CAT), glutathione (GR), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione disulphide (GSSG) and lipid peroxidation (LPO). Meta-analyses showed that moderate-volume PE significantly reduced LPO (SMD = −2.41; 95% CI: −3.89 to −0.93), while high-volume PE increased LPO (SMD = 4.55; 95% CI: 1.92 to 7.18). Low-intensity or low-volume PE did not significantly alter oxidative markers.

Conclusions

PE induces either adaptive or maladaptive biochemical neuroplasticity in the cerebellum depending on protocol variables. While enzymatic activity responds to cellular changes and limits nervous tissue protection, adaptive biochemical neuroplasticity seems to confer greater resistance and efficiency.

Introduction

Neuroplasticity refers to the CNS’s ability to reorganize and adapt structurally and functionally in response to environmental stimuli or injury [1,2]. At the cellular and molecular levels, neuroplasticity encompasses alterations in neuronal structure and function, including synaptic remodeling and pathways reorganization [1]. These changes can be beneficial (adaptive neuroplasticity) or detrimental (maladaptive neuroplasticity) depending on their impact on CNS integrity and function [3,4]. Biochemical neuroplasticity refers to neurochemical alterations in response to stimuli such as physical exercise (PE), which can lead to oxidative stress that affects neuronal integrity [5]. Although neuroplasticity encompasses several neuronal events, the terms adaptive or maladaptive biochemical neuroplasticity can address changes in cerebellar oxidative biochemistry.

Adaptive biochemical neuroplasticity is associated with enhanced neuroprotection, memory, and motor function. Conversely, maladaptive responses involve an oxidative imbalance in the nervous tissue that damages the mitochondrial energetic function and proteins/enzymes and lipids of the cell membrane, which leads to oxidative stress, cell death, and functional damage [6]. Environmental stimuli [7], food [8], alcohol consumption [9], and PE can induce biochemical neuroplasticity [10,11].

PE-associated improvements in cognitive domains such as memory [12], reaction time [13], and motor learning [14] may result from the modulation of enzymes, including superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione disulfide (GSSG), and glutathione peroxidase (GSH-Px), as well as changes in lipid peroxidation (LPO) across various brain regions, such as the motor cortex, hippocampus, brainstem, and cerebellum [15,16]. However, these health benefits are dependent on the intensity, volume, and frequency of PE [17,18].

PE is strongly associated with cerebellar functions that regulate postural control, coordination, planning, learning, and motor execution [19]. The high energetic demand of cerebellar neurons – required to receive and project axons to various cortical areas including posterior parietal, prefrontal, and primary motor regions – increases the formation of reactive oxygen species (ROS). Consequently, the cerebellum is particularly susceptible to biochemical alterations resulting from the increased energy expenditure induced by PE [20].

Although low-intensity PE surprisingly does not appear to induce cerebellar neuroplasticity [21], high volumes of moderate-intensity PE may result in maladaptive biochemical responses and neural tissue damage [10]. Thus, professionals employing PE for high-performance sports training, health promotion, or therapeutic purposes must have a clear understanding of the relationship between PE parameters and biochemical neuroplasticity. This systematic review and meta-analysis were therefore conducted to evaluate the effects of PE on cerebellar biochemical neuroplasticity.

Materials and methods

This systematic review and meta-analysis was registered in the Open Science Framework (OSF) database under record 10.17605/OSF.IO/ERBD2 (access at https://osf.io/erbd2/) and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines (see S1 File) [22].

Inclusion and exclusion criteria

This review followed the PICO strategy:

Population (P). Experimental studies involving small rodents

Intervention (I). PE protocols with well-defined volume, intensity, and frequency.

Comparator (C). Small rodents not subjected to PE.

Outcome (O). Biochemical changes in cerebellar nervous tissue following PE.

Study design.

Eligible studies were original in vivo experimental investigations that assessed the biochemical effects of PE on the cerebellum of small rodents using well-defined training protocols in terms of volume, intensity, and frequency.

Inclusion criteria.

1. (1). Title and/or abstract containing relevant descriptors.

2. (2). No language restrictions.

3. (3). Original studies.

4. (4). In vivo models with small rodents.

5. (5). Evaluation of cerebellar biochemical changes resulting from PE protocols with well-defined volume, intensity, and frequency.

Exclusion criteria.

Reviews, case reports, descriptive studies, opinions, technical articles, guidelines, and in vitro studies were excluded.

Search strategy

The MeSH descriptors “animal”, “brain”, “exercise”, “physical fitness”, and “oxidative stresses” were used. The search was slightly adapted for each database as detailed in S2 and S3 Files. Search alerts were configured to notify authors of newly published studies. Two reviewers (MGC and TAL) conducted independent database searches.

Information sources

Studies published between January 1976 and July 2024 were searched in PubMed, Scopus, Web of Science, and Cochrane Central, with no language restrictions.

Screening and data extraction

Duplicate records and those lacking relevant MesH descriptors in the title or abstract were excluded using the Rayyan platform (https://new.rayyan.ai/). Full-text reading and selection were independently performed by two reviewers (MGC and TAL), with disagreements resolved by a third reviewer (CB) (S2 and S3 Files). Extracted data included: author, study, design, exercise protocol, enzymatic assessment, oxidative damage assessment, method of stress induction, results, conclusions, reviewer, date, and third reviewer (S4 File). A summary of the included studies is provided in Table 1.

[Figure omitted. See PDF.]

Critical appraisal of individual sources of evidence

Methodological quality and risk of bias were independently evaluated by two reviewers (MGC and TAL) using the SYRCLE tool, which is adapted from the Cochrane RoB tool for animal studies (S5 File) [23]. Ten domains were assessed: (a) sequence allocation; (b) baseline group similarity or confounders adjustment; (c) random allocation; (d) random housing conditions; (e) blinding of caregivers/investigators; (f) random outcome assessment, (g) blinding of outcome assessor; (h) handling of incomplete data; (i) absence of selective outcome reporting; and (j) other sources of bias. Each domain was evaluated by answering several questions namely ‘yes’, ‘probably yes’, ‘no’, ‘probably no’, ‘no information’, or ‘not applicable’, and then rated as ‘high’, ‘low’, or ‘unclear’. Studies were deemed low risk of bias if all domains were rated as low, while studies rated as high or unclear for at least one domain were deemed high or unclear risk of bias, respectively. This tool assessed whether the methods were adequate to provide consistent and valid information, as well as whether the results revealed the expected effects.

Data analysis

Descriptive synthesis.

We summarized findings for SOD, CAT, GSH, and LPO based on structured extraction from original studies investigating biochemical changes in cerebellar tissue after PE.

Quantitative synthesis.

When two or more studies were available, meta-analyses were conducted for SOD, CAT, GSH, and LPO by using review manager software (RevMan 5.4, The Cochrane Collaboration; Copenhagen, Denmark) [24]. Meta-analyses were stratified by PE volumes and only considered the studies in which the animals completed the PE protocols. Sample size, means, and standard deviations were used to compare groups (PE versus control). When raw data were only available in graphical form (i.e., data also absent in supplementary material), numerical estimates were derived using validated software (WebPlotDigitizer) [25]. Effect sizes were computed using a random-effects model and the inverse variance method. The standardized mean difference (SMD) and 95% confidence intervals (CIs) (p < 0.05) were reported. Effect sizes were interpreted as small (SMD < 0.40), moderate (SMD = 0.41–0.70), or large (SMD > 0.70) (26–28). Heterogeneity was assessed using the I² statistic and interpreted as low (~25%), moderate (~50%), or high (~75%) [24]. Funnel plots were used to assess potential publication bias (see S6 File), and forest plots displayed effect sizes for each outcome [24–28].

Results

Study selection

From 3,107 initial records, 767 duplicates were excluded and 2,330 records were excluded after title and abstract screening. Among 10 records selected for full-text reading, one study was excluded for lacking an exercise group, one study was excluded due to the absence of cerebellar oxidative stress-related outcomes, and two studies were excluded for evaluating spontaneous PE. Finally, six animal studies were included for qualitative and quantitative analysis [10,14,15,21,29,30], see Fig 1 and S3 File.

[Figure omitted. See PDF.]

Study characteristics

SOD was evaluated in five studies [10,15,21,29,30], CAT was assessed in four studies [10,15,29,30], GSH was determined in four studies [10,14,15,30], GSH-Px was evaluated in two studies [15,30], GSSG was assessed in three studies [10,15,30], and GR was determined in two studies [15,30]. The six studies evaluated LPO [10,14,15,21,29,30] and two studies used ethanol to induce oxidative stress [14,15].

Risk of Bias

The studies exhibited a low and unclear risk of bias for eight (a, b, c, d, f, h, i, and j) and two domains (e and g), respectively. No study was deemed at high risk of bias in any domain.

Individual study results

In two studies, PE promoted cerebellar neuroprotection against ethanol-induced damage [14,15]. Low- and moderate-intensity PE were performed on running treadmills for four [14], six [15,29,30], or twelve weeks [10,21]. High-intensity PE was not evaluated in any study. The PE volumes ranged from 15 to 90 minutes per day, with a frequency of 3–5 days per week (Table 1).

Overall, PE increased the activity of SOD, CAT, GR, and GSH [10,15,30], while GSSG activity did not changed [9,13,14]. Furthermore, PE reduced LPO in four studies [10,14,15,30], increased LPO in two studies [10,30], and did not change LPO in one study [21] (Table 2).

[Figure omitted. See PDF.]

Quantitative analysis

The meta-analyses for high- and moderate-volume PE are respectively shown in Figs 4 and 5. For high-volume PE, both SOD and CAT activities were not significantly different from their respective controls, and high heterogeneity among studies was observed (SOD overall effect = 0.65; 95%CI 0.74, −1.48 to 2.97; I² = 87%/ CAT overall effect = 0.74; 95%CI 1.33, −2.18 to 4.85; I² = 93%). In addition, LPO was significantly higher than control, and moderate heterogeneity among studies was observed (LPO overall effect = 3.39; 95%CI 4.55, 1.92 to 7.18; I² = 43%) (Fig 4).

[Figure omitted. See PDF.]

Green, yellow, and red circles indicate low, unclear, and high risk of bias, respectively.

[Figure omitted. See PDF.]

For moderate-volume PE, SOD, CAT, and GSH activities were not significantly different from their respective controls (SOD overall effect = 1.17; 95%CI −0.86, −2.29 to 0.58; CAT overall effect = 0.62; 95%CI −0.19, −0.79 to 0.41; GSH overall effect = 1.52; 95%CI 0.53, −0.15 to 1.22). The heterogeneity among studies was low for CAT and GSH (I² = 0% and I² = 20%, respectively) and high for SOD (I² = 84%). In addition, LPO was significantly lower than the control (LPO overall effect = 2.67; 95%CI −1.94, −3.37 to −0.51) and high heterogeneity among studies was observed (I² = 84%) (Fig 5).

Discussion

This review applied eligibility criteria for study selection (Fig 1) methods to reduce the risk of bias (Figs 2 and 3), and quantitative syntheses (Figs 4 and 5) to provide valuable conclusions regarding PE-induced cerebellar biochemical neuroplasticity [22]. Experimental studies using animal models provide consistent and reliable evidence of the biochemical alterations underlying neuroplasticity and the effects of PE protocols on health conditions.

Neuroplasticity is typically preceded by biochemical alterations, which appear to be key mechanisms that can either improve neural function or cause cell death [6]. Alterations in enzymatic activities and consequential neurophysiological effects must be understood as biochemical neuroplasticity, the induction of which by PE was demonstrated in this review. Interestingly, variations in the PE protocol can either increase or decrease the activity of antioxidant enzymes and LPO [10]. Given the complexity of biochemical systems, PE can promote either adaptive or maladaptive biochemical neuroplasticity (Figs 4–6). As shown in the meta-analysis of moderate-volume PE (Fig 5), increased O₂ consumption for short periods can significantly increase ROS formation and prevent the reestablishment of neural homeostasis by enzymes. Nevertheless, moderate ROS formation also acts as signaling stimuli that enhance antioxidant defenses [10,15,30] and affects adaptive neuroplasticity-related factors such as BDNF, FGF, VGF, and angiogenesis [31]. In contrast, excessive ROS formation due to prolonged O₂ consumption during high-volume PE (Fig 5) may overwhelm antioxidant systems, increase LPO, and cause oxidative stress, which impairs energy metabolism, induces cell death, or triggers neuroinflammatory responses – hallmarks of maladaptive biochemical neuroplasticity [9].

Modulation of LPO [10,14,15,29,30] and enzymes activities involved in cerebellar metabolic pathways – such as SOD, CAT, GR, GSH, and GSH-Px [10,15,29,30] – were reported in the selected studies as evidence of adaptive biochemical neuroplasticity induced by moderate-intensity PE (Table 1). This meta-analysis revealed that moderate-volume PE did not significantly modulate antioxidant enzyme levels but did significantly reduce LPO [10,14,15,30]. In contrast, LPO increased following high-volume PE [10] (Figs 4 and 5). The high heterogeneity among studies may be attributed to subtle variations in training frequency, volume, or intensity (speed), emphasizing the need for further investigation into the biochemical effects of different PE protocols on cerebellar biochemical neuroplasticity. Conversely, biochemical neuroplasticity was not observed in animals subjected to low-intensity PE protocols [21], see Tables 1 and 2, and Fig 6. Frequency alone did not appear to cause biochemical alterations since protocols with 5 training days per week yielded divergent effects depending on total PE volume [10,14], see Fig 6. It is important to note that studies involving elderly animals and muscle strength training were not included in this review and may yield different cerebellar responses. All selected studies reported aerobic treadmill protocols and presented no high risk of bias in key domains (Fig 2).

PE does not appear to modulate antioxidant enzyme activity in a linear fashion. While some studies reported increased SOD, CAT, GSH, and GR activity [10,15,30], others revealed reduced SOD, CAT, and GSH-Px levels [14,30]. These discrepancies likely reflect transient ROS elevations due to increased energy demands from PE (Table 2). Although excessive ROS levels can damage neurons, moderate levels are essential for neuronal signaling and neuroplasticity [32]. The CNS can tolerate brief ROS increases [33], which activate transcription factors such as Forkhead box O [34,35] that upregulates genes involved in cell survival and differentiation, cell cycle arrest, oxidative stress resistance, and adaptive neuroplasticity [35,36]. This super-compensation mechanism may enhance cerebellar resistance.

Additionally, PE stimulates the expression of neurotrophic factors related to CNS plasticity, such as insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). These factors reduce oxidative stress by optimizing cellular functions, regulating mitochondrial energy homeostasis, and promoting synaptic regulation [31]. For instance, increased BDNF expression via the PGC-1alpha/FNDC5/irisin pathway [31,37,38] activates the TrkB/BDNF pathway, which activates TrkB tyrosine kinase receptors, and reduces ROS formation [39]. The CREB-BNDF pathway is sensitive to redox reactions and closely linked to the oxidative stress regulatory mechanism since it induces the activation of APE-1 (an inflammation regulator that modulates ROS levels) and thus promotes adaptive biochemical neuroplasticity [2,40,41]. Moreover, BDNF also affects proteasome function, which protects against oxidative stress by degrading damaged and oxidized proteins [42], and thus characterizes adaptive biochemical neuroplasticity (Fig 4).

Neurophysiological responses to PE vary by CNS region [15] and are influenced by intensity, volume, and frequency [17]. Although low-intensity PE does not appear to affect cerebellar biochemical neuroplasticity [21], high-volume PE increases oxidative stress and promotes maladaptive biochemical neuroplasticity [10], see Fig 6. The selected articles reported total running distances to define PE parameters [17]. Volume, intensity, and frequency are adequate variables for accurately assessing PE-induced neuroplasticity [18].

Two studies linked oxidative stress to high-volume PE [10,30]. In one, a single 90-minute PE session increased cerebellar LPO and triggered oxidative stress [10] (see Table 1). Prolonged O₂ consumption during PE increases the amount of free radicals and induces phosphorylation of the electron transport chain [43]. The lost electrons in the mitochondria generate superoxide (O_2-), hydrogen peroxide (H₂O₂), and hydroxyl (OH) radicals [44,45]. Elevated cerebellar ROS levels impair mitochondrial energetic activity, which modulates redox signaling pathways and causes oxidative imbalance [20]. These events can promote chronic damage in nervous tissue that can lead to cell death and impair cognitive and motor functions [2,14], classifying them as maladaptive biochemical neuroplasticity. Therefore, PE volume plays a pivotal role in determining the direction of cerebellar neuroplasticity.

The threshold at which PE transitions from adaptive to maladaptive neuroplasticity remains unclear and warrants further investigation. This review shows that high-volume PE increases LPO and the risk of maladaptive changes [10], see Figs 4 and 6. However, PE may protect against ethanol-induced oxidative stress in the cerebellum [14].

While oxygen is essential for cellular function, excessive consumption can generate toxic ROS and disrupt biochemical homeostasis [46]. Moderate ROS increases induced by moderate-volume PE are within physiological norms and support adaptive responses [10,46,47]. In contrast, excessive mitochondrial ROS levels (as observed in several diseases) damage lipids, proteins, and DNA, which impairs the maintenance of membrane potential, transmembrane transport, proteostasis, and enzymatic activities [48,49]. These detrimental effects may also occur following prolonged moderate PE.

PE protocols involving less than 80 minutes per day at 5 days per week were effective in reducing LPO and improving some antioxidant activities [10,15,30] (see Table 1). PE activates the PGC-1α pathway, which regulates mitochondrial biogenesis [6], enhances cellular energy metabolism, and increases the cerebellum’s resistance to oxidative stress – hallmarks of adaptive biochemical neuroplasticity.

Moderate PE can also attenuate ethanol-induced maladaptive neuroplasticity in the cerebellum (see Table 1). Two studies reported ethanol-induced oxidative stress, which is metabolized to acetaldehyde by the enzyme cytochrome P4502E1 in different CNS regions [50–52]. Damage to DNA, proteins, and particularly highly unsaturated phospholipids modifies the structure and function of neuronal plasma membranes [53]. High cerebellar ROS levels jeopardize H₂O₂ decomposition by the P4502E1 enzyme due to iron loss at the catalytic site. In addition, loss of NaDPH cosubstrate impairs the elimination of peroxides formed by ethanol-induced oxidative stress [52], see Fig 5. However, the combination of moderate PE and ethanol consumption promotes a synergistic increase in cytochrome P4502E1 activity as a compensatory response that may be related to a neuroprotective mechanism [14,54]. Excessive ROS levels stimulate the expression of neurotrophic factors while moderate PE regulates energy homeostasis and improves mitochondrial function, which increases the expression of BDNF, FGF, and VEGF [49]. High levels of these factors activate regulatory mechanisms that prevent ethanol-induced oxidative imbalance and thus can be considered adaptive neuroplasticity [55–57], see Fig 7.

[Figure omitted. See PDF.]

[Figure omitted. See PDF.]

[Figure omitted. See PDF.]

[Figure omitted. See PDF.]

Cerebellar biochemical alterations appear to be strongly influenced by PE intensity. No significant alterations were observed following low-intensity PE (~50% of maximal speed) [21], whereas moderate-intensity PE (~70% of maximal speed) significantly reduced cerebellar LPO [14,15], suggesting adaptive neuroplasticity (Fig 6). Although none of the included studies investigated high-intensity PE (Table 1), previous research suggests that CNS can tolerate high O₂ consumption only for short periods [15]. According to the American College of Sports Medicine, precise PE variables are essential. Protocols with moderate intensity, duration <80 minutes per day, and frequency of 3–5 days per week appear optimal for inducing adaptive cerebellar neuroplasticity (Table 1). In contrast, high-volume PE (e.g., 90 minutes per day and 5 days per week) induced maladaptive neuroplasticity, representing potential health risks (Figs 6 and 8).

[Figure omitted. See PDF.]

Fine-tuning PE protocols may enhance both the safety and effectiveness of exercise-induced adaptive neuroplasticity. However, this review is limited by the absence of studies evaluating high-intensity protocols. Small sample sizes and between-study heterogeneity may have affected the meta-analytic outcomes, especially for SOD (I² 79%) and LPO (I² 81%) in the moderate-volume group, and SOD (I² 87%), CAT (I² 93%), and LPO (I² 43%) in the high-volume group. While protocol variability (e.g., 4–12 weeks of training) may have contributed to heterogeneity (see Figs 4 and 5), the aerobic-endurance nature of all PE interventions supports the consistency of the neurophysiological responses observed [58].

Human studies using biomarkers and biological fluid components (e.g., SOD, CAT, and GPx) and non-enzymatic antioxidants (e.g., GSH and uric acid) have similarly demonstrated that PE intensity, volume, and frequency determine oxidative responses [59–61]. As observed in the animal studies included in this systematic review, low-intensity PE does not significantly alter ROS levels, whereas moderate-to-high-intensity PE performed at moderate volumes reduces oxidative stress and increases antioxidant defenses.

The adaptive/maladaptive neuroplasticity patterns observed in small rodents also appear in humans [59,62]. Moderate PE decreases MDA levels in peripheral blood and increases plasma CAT, SOD, and GPx activity [59,62]. These findings in humans confirm the cerebellar tissue responses observed in small rodents following moderate PE.

Conclusion

PE induces either adaptive or maladaptive biochemical neuroplasticity in the cerebellum depending on protocol variables. Low-intensity PE does not induce significant changes, whereas high-volume PE may lead to maladaptive neuroplasticity. In contrast, moderate-volume, moderate-intensity PE performed three to five days per week efficiently promotes adaptive neuroplasticity and protects the cerebellum against oxidative stress. While enzymatic activity responds to cellular changes and limits nervous tissue protection, adaptive biochemical neuroplasticity seems to confer greater resistance and efficiency.

Supporting information

S1 File. PRISMA checklist.

https://doi.org/10.1371/journal.pone.0309259.s001

(DOCX)

S2 File. Search Strategy and Study selection.

https://doi.org/10.1371/journal.pone.0309259.s002

(DOCX)

S3 File. Study selection.

https://doi.org/10.1371/journal.pone.0309259.s003

(XLSX)

S4 File. Data collection.

https://doi.org/10.1371/journal.pone.0309259.s004

(XLSX)

S5 File. Risk of bias for individual studies.

https://doi.org/10.1371/journal.pone.0309259.s005

(XLSX)

S6 File. Funnel plots.

https://doi.org/10.1371/journal.pone.0309259.s006

(DOCX)

Acknowledgments

The Deans of Undergraduate and Research/Postgraduate Studies of the Federal University of Pará and the Brazilian Agency for Support and Evaluation of Graduate Education (CAPES) supported this review.

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53. 53. Reddy VD, Padmavathi P, Kavitha G, Saradamma B, Varadacharyulu N. Alcohol-induced oxidative/nitrosative stress alters brain mitochondrial membrane properties. Mol Cell Biochem. 2012;375(1–2):39–47.

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* Google Scholar

54. 54. Ardies CM, Zachman EK, Koehn BJ. Effect of swimming exercise and ethanol on rat liver P450-dependent monooxygenases. Med Sci Sports Exerc. 1994;26(12):1453–8. pmid:7869878

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* PubMed/NCBI

* Google Scholar

55. 55. Fernandes LMP, Cartágenes SC, Barros MA, Carvalheiro TCVS, Castro NCF, Schamne MG. Repeated cycles of binge-like ethanol exposure induce immediate and delayed neurobehavioral changes and hippocampal dysfunction in adolescent female rats. Behav Brain Res. 2018;350:99–108.

* View Article

* Google Scholar

56. 56. Saraulli D, Costanzi M, Mastrorilli V, Farioli-Vecchioli S. The long run: neuroprotective effects of physical exercise on adult neurogenesis from youth to old age. Curr Neuropharmacol. 2017;15(4):519–33. pmid:27000776

* View Article

* PubMed/NCBI

* Google Scholar

57. 57. Bo H, Jiang N, Ji LL, Zhang Y. Mitochondrial redox metabolism in aging: effect of exercise interventions. J Sport Health Sci. 2013;2(2):67–74.

* View Article

* Google Scholar

58. 58. Hughes DC, Ellefsen S, Baar K. Adaptations to endurance and strength training. Cold Spring Harb Perspect Med. 2018;8(6):a029769. pmid:28490537

* View Article

* PubMed/NCBI

* Google Scholar

59. 59. Pingitore A, Lima GPP, Mastorci F, Quinones A, Iervasi G, Vassalle C. Exercise and oxidative stress: potential effects of antioxidant dietary strategies in sports. Nutrition. 2015;31(7–8):916–22. pmid:26059364

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* Google Scholar

60. 60. Vassalle C, Pingitore A, De Giuseppe R, Vigna L, Bamonti F. Biomarkers Part II: biomarkers to estimate bioefficacy of dietary/supplemental antioxidants in sport. Antioxidants Sport Nutr. 2015.

61. 61. Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44–84.

* View Article

* Google Scholar

62. 62. Mota MP, Dos Santos ZA, Soares JFP, de Fátima Pereira A, João PV, O’Neil Gaivão I, et al. Intervention with a combined physical exercise training to reduce oxidative stress of women over 40 years of age. Exp Gerontol. 2019;123:1–9. pmid:31102617

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Citation: Corrêa MG, Lobão TA, Bahia GMdC, Aires EMS, Gomes RdC, Medeiros de Queiroz JH, et al. (2025) Biochemical neuroplasticity in the cerebellum after physical exercise: Systematic review and meta-analysis. PLoS One 20(8): e0309259. https://doi.org/10.1371/journal.pone.0309259

About the Authors:

Marcio Gonçalves Corrêa

Contributed equally to this work with: Marcio Gonçalves Corrêa, Thais Alves Lobão

Roles: Conceptualization, Investigation, Methodology, Writing – original draft

Affiliation: Laboratory of Neuroplasticity – Health Institute Sciences, UFPA, Pará, Brazil

Thais Alves Lobão

Contributed equally to this work with: Marcio Gonçalves Corrêa, Thais Alves Lobão

Roles: Conceptualization, Formal analysis, Investigation, Writing – original draft

Affiliation: Laboratory of Neuroplasticity – Health Institute Sciences, UFPA, Pará, Brazil

Gabriel Mesquita da Conceição Bahia

Roles: Data curation, Formal analysis, Methodology, Writing – original draft

Affiliation: Laboratory of Neuroplasticity – Health Institute Sciences, UFPA, Pará, Brazil

ORICD: https://orcid.org/0000-0003-3820-0131

Erica Miranda Sanches Aires

Roles: Data curation, Formal analysis, Investigation, Methodology

Affiliation: Laboratory of Neuroplasticity – Health Institute Sciences, UFPA, Pará, Brazil

Rebeca da Costa Gomes

Roles: Data curation, Formal analysis, Investigation

E-mail: [email protected], [email protected] (CPB); [email protected] (RDCG)

Affiliation: Laboratory of Neuroplasticity – Health Institute Sciences, UFPA, Pará, Brazil

Jeffeson Hildo Medeiros de Queiroz

Roles: Data curation, Formal analysis, Investigation, Methodology, Writing – original draft

Affiliation: Laboratory of Neuroplasticity – Health Institute Sciences, UFPA, Pará, Brazil

ORICD: https://orcid.org/0000-0002-3209-5679

Marta Chagas Monteiro

Roles: Formal analysis, Funding acquisition, Writing – review & editing

Affiliation: Laboratory of Laboratory Immunology, Microbiology, and In Vitro Assays – Health Institute Sciences, UFPA, Pará, Brazil

Carlomagno Pacheco Bahia

Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Supervision, Visualization, Writing – review & editing

E-mail: [email protected], [email protected] (CPB); [email protected] (RDCG)

Affiliation: Laboratory of Neuroplasticity – Health Institute Sciences, UFPA, Pará, Brazil

ORICD: https://orcid.org/0000-0003-3794-4710

[/RAW_REF_TEXT]

[/RAW_REF_TEXT]

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30. Chalimoniuk M, Jagsz S, Sadowska-Krepa E, Chrapusta SJ, Klapcinska B, Langfort J. Diversity of endurance training effects on antioxidant defenses and oxidative damage in different brain regions of adolescent male rats. J Physiol Pharmacol. 2015;66(4):539–47. pmid:26348078

31. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. Exercise Induces Hippocampal BDNF through a PGC-1α/FNDC5 Pathway. Cell Metab. 2013;18(5):649–59.

32. Radak Z, Suzuki K, Higuchi M, Balogh L, Boldogh I, Koltai E. Physical exercise, reactive oxygen species and neuroprotection. Free Radic Biol Med. 2016;98:187–96. pmid:26828019

33. Maniscalco JW, Rinaman L. Interoceptive modulation of neuroendocrine, emotional, and hypophagic responses to stress. Physiol Behav. 2017;176:195–206.

34. Slopack D, Roudier E, Liu STK, Nwadozi E, Birot O, Haas TL. Forkhead BoxO transcription factors restrain exercise-induced angiogenesis. J Physiol. 2014;592(18):4069–82. pmid:25063823

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38. Albrahim T, Alangry R, Alotaibi R, Almandil L, Alburikan S. Effects of regular exercise and intermittent fasting on neurotransmitters, inflammation, oxidative stress, and brain-derived neurotrophic factor in cortex of ovariectomized rats. Nutrients. 2023;15(19):4270. pmid:37836554

39. Pringle AK, Sundstrom LE, Wilde GJC, Williams LR, Lannotti F. Brain-derived neurotrophic factor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures. Neurosci Lett. 1996;211(3):203–6.

40. Yang J-L, Lin Y-T, Chuang P-C, Bohr VA, Mattson MP. BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1. Neuromolecular Med. 2014;16(1):161–74. pmid:24114393

41. Grösch S, Kaina B. Transcriptional activation of apurinic/apyrimidinic endonuclease (Ape, Ref-1) by oxidative stress requires CREB. Biochem Biophys Res Commun. 1999;261(3):859–63. pmid:10441516

42. Jia J-M, Chen Q, Zhou Y, Miao S, Zheng J, Zhang C, et al. Brain-derived neurotrophic factor-tropomyosin-related kinase B signaling contributes to activity-dependent changes in synaptic proteins. J Biol Chem. 2008;283(30):21242–50. pmid:18474605

43. Kudin AP, Malinska D, Kunz WS. Sites of generation of reactive oxygen species in homogenates of brain tissue determined with the use of respiratory substrates and inhibitors. Biochim Biophys Acta. 2008;1777(7–8):689–95. pmid:18510942

44. Damasceno DC, Volpato GT, Paranhos Calderon I de M, Cunha Rudge MV. Oxidative stress and diabetes in pregnant rats. Anim Reprod Sci. 2002;72(3–4):235–44.

45. Collin F. Chemical basis of reactive oxygen species reactivity and involvement in neurodegenerative diseases. Int J Mol Sci. 2019;20(10):2407.

46. Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21(7):363–83. pmid:32231263

47. Hamanaka RB, Chandel NS. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem Sci. 2010;35(9):505–13. pmid:20430626

48. Radak Z, Chung HY, Koltai E, Taylor AW, Goto S. Exercise, oxidative stress and hormesis. Ageing Res Rev. 2008;7(1):34–42. pmid:17869589

49. Pesta D, Roden M. The Janus head of oxidative stress in metabolic diseases and during physical exercise. Curr Diab Rep. 2017;17(6):41. pmid:28439848

50. Warner M, Gustafsson JA. Effect of ethanol on cytochrome P450 in the rat brain. Proc Natl Acad Sci U S A. 1994;91(3):1019–23. pmid:8302826

51. Hansson T, Tindberg N, Ingelman-Sundberg M, Köhler C. Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system. Neuroscience. 1990;34(2):451–63. pmid:2333153

52. Hipolito L, Sanchez M, Polache A, Granero L. Brain metabolism of ethanol and alcoholism: an update. Curr Drug Metab. 2007;8(7):716–27.

53. Reddy VD, Padmavathi P, Kavitha G, Saradamma B, Varadacharyulu N. Alcohol-induced oxidative/nitrosative stress alters brain mitochondrial membrane properties. Mol Cell Biochem. 2012;375(1–2):39–47.

54. Ardies CM, Zachman EK, Koehn BJ. Effect of swimming exercise and ethanol on rat liver P450-dependent monooxygenases. Med Sci Sports Exerc. 1994;26(12):1453–8. pmid:7869878

55. Fernandes LMP, Cartágenes SC, Barros MA, Carvalheiro TCVS, Castro NCF, Schamne MG. Repeated cycles of binge-like ethanol exposure induce immediate and delayed neurobehavioral changes and hippocampal dysfunction in adolescent female rats. Behav Brain Res. 2018;350:99–108.

56. Saraulli D, Costanzi M, Mastrorilli V, Farioli-Vecchioli S. The long run: neuroprotective effects of physical exercise on adult neurogenesis from youth to old age. Curr Neuropharmacol. 2017;15(4):519–33. pmid:27000776

57. Bo H, Jiang N, Ji LL, Zhang Y. Mitochondrial redox metabolism in aging: effect of exercise interventions. J Sport Health Sci. 2013;2(2):67–74.

58. Hughes DC, Ellefsen S, Baar K. Adaptations to endurance and strength training. Cold Spring Harb Perspect Med. 2018;8(6):a029769. pmid:28490537

59. Pingitore A, Lima GPP, Mastorci F, Quinones A, Iervasi G, Vassalle C. Exercise and oxidative stress: potential effects of antioxidant dietary strategies in sports. Nutrition. 2015;31(7–8):916–22. pmid:26059364

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62. Mota MP, Dos Santos ZA, Soares JFP, de Fátima Pereira A, João PV, O’Neil Gaivão I, et al. Intervention with a combined physical exercise training to reduce oxidative stress of women over 40 years of age. Exp Gerontol. 2019;123:1–9. pmid:31102617